Many brain diseases in their early stages do not involve defects in the BBB, but are characterized by changes in regional perfusion patterns. Measurement of these physiological changes can provide useful diagnostic information on brain function. In order to develop an effective and low cost agent for brain perfusion imaging, suitable radiopharmaceuticals, preferably Tc-99m labeled compounds, which localize in brain are absolutely essential. This proposal is aimed at the development of brain perfusion imaging agents which are easily prepared and suitable for routine use in nuclear medicine clinics. The new Tc-99m brain agents are based on our proposed "pH shift" mechanism which has been successfully applied in the design of Se-75 and I-123 labeled brain imaging agents. Many tissues or organs, including brain cells, have decreased intracellular pH either normally or as a result of various metabolic disturbances. Amines which are neutral and lipid soluble at blood pH (7.4) can diffuse freely into cells. In those regions where intracellular pH is lower (7.0), the amines combine with hydrogen ions and become positively charged. In this form the molecules are no longer lipid soluble and are temporarily "trapped" because they cannot diffuse out of the cell. The ligands we propose are designed to form stable and neutral Tc-99m complexes at high pH and contain extra substituted amine groups for "pH shift" trapping in brain. The proposed Tc-99m complexes will be subjected to a battery of tests including: measurement of physicochemical properties, biodistribution studies, imaging studies and studies of regional distribution in brain with autoradiographic technique, etc.